PB1961: INVOLVEMENT OF IMMUNITY IN THE CONTINUATION OF TFR AFTER BOSTINIB DISCONTINUATION
Authors: Yuki Fujioka, Takaaki Ono, Naoto Takahashi
Journal: HemaSphere (2023)

Topic: 7. Chronic myeloid leukemia - Biology & Translational Research Background: Treatment-free remission (TFR) is now considered the goal in the treatment of chronic myeloid leukemia (CML). The first imatinib discontinuation trial in 2010 showed that TFR can be achieved in some CML patients, and more recently many discontinuation trials with second-generation tyrosine kinase inhibitors (2G-TKIs) such as nilotinib or dasatinib have been conducted. As 2G-TKIs can achieve deeper remissions earlier than imatinib, it is expected that TFR can be achieved in more patients with shorter TKI durations. Bostinib, the latest 2G-TKI, is a clinically accessible drug with a low incidence of cardiovascular adverse effects, but there are still few reports on TFR. We have analyzed immune responses during the TFR phase in discontinuation studies after imatinib, nilotinib and dasatinib and found that regulatory T cells (Treg) increased after TKI discontinuation in populations with long-term continuation of TFR with imatinib and dasatinib. On the other hand, lymphocytes are not affected by nilotinib, but the involvement of monocyte lineage cells in the maintenance of TFR has been suggested (unpublished data). In this study, we performed a similar analysis of immunity in chronic phase CML (CML-CP) patients who discontinued treatment with bostinib after a deep remission, to investigate the involvement of bostinib in the immune response in the continuation of TFR. Aims: To analyze the immune profile during the TFR phase after discontinuation of bostinib and to investigate the role of bostinib in the continuation of TFR. Methods: Patients with CML-CP who were treated with bostinib and had a confirmed deep molecular remission (DMR, deeper than MR4.5) before discontinuation of bostinib were included. We collected patients peripheral blood samples before bostinib discontinuation and at 1, 3, 6 and 12 months after discontinuation (Figure 1). Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed for immunophenotype by flow cytometry. We divided the patients into two groups: the TFR group who maintained TFR for more than 12 months, and the retreatment group who had relapsed within 12 months. Relapse was defined as loss of MMR (MR3.0). Results: Of the twelve CML-CP patients challenged with TFR after treatment with bostinib, seven (58.3%) were able to maintain TFR at 12 months (Figure 2). In a small number of cases, a comparison of the TFR group with the retreatment group showed no difference in T cells, CD4+ T cells, CD8+ T cells, B cells, CD56dimNK cells and myeloid-derived suppressor cells (MDSC). In FoxP3hiCD45RA- effector regulatory T cells (eTreg) and CD56highNK cells, these value before discontinuation tended to be higher in the TRF group. Kinetics of eTreg showed an increase at 1 month after discontinuation in the TFR group, but no change in the retreatment group (Figure 3). Summary/Conclusion: With bostinib, as with other TKIs, TFR was achieved at a constant rate. Analysis of immune cells during the TFR phase showed an increase in eTreg at 1 month after discontinuation, similar to imatinib and dasatinib. The mechanism of this is being investigated, but it may be an indicator that host anti-tumour immunity is maintained during long-term TKI exposure. In other words, the increase in Tregs does not imply immunosuppression, but rather a residual immune response, including host anti-tumour immunity. Therefore, although bostinib also acts on lymphocytes and prolonged exposure is thought to exhaust the host immune system, it is possible that the residual immune capacity during the TFR phase may be beneficial.Keywords: Chronic myeloid leukemia, Tyrosine kinase inhibitor, treatment-free remission, Regulatory T cell